Faculty Collaboration Database

MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice. Blood 2015 Sep 10;126(11):1314-23

Date

07/04/2015

Pubmed ID

26138686

Pubmed Central ID

PMC4566810

DOI

10.1182/blood-2015-02-627356

Scopus ID

2-s2.0-84942512521 (requires institutional sign-in at Scopus site)   52 Citations

Abstract

MicroRNAs (miRs) play important roles in orchestrating many aspects of the immune response. The miR-17-92 cluster, which encodes 6 miRs including 17, 18a, 19a, 20a, 19b-1, and 92-1, is among the best characterized of these miRs. The miR-17-92 cluster has been shown to regulate a variety of immune responses including infection, tumor, and autoimmunity, but the role of this cluster in T-cell response to alloantigens has not been previously explored. By using major histocompatibility complex (MHC)-matched, -mismatched, and haploidentical murine models of allogeneic bone marrow transplantation (allo-BMT), we demonstrate that the expression of miR-17-92 on donor T cells is essential for the induction of graft-versus-host disease (GVHD), but dispensable for the graft-versus-leukemia (GVL) effect. The miR-17-92 plays a major role in promoting CD4 T-cell activation, proliferation, survival, and Th1 differentiation, while inhibiting Th2 and iTreg differentiation. Alternatively, miR-17-92 may promote migration of CD8 T cells to GVHD target organs, but has minimal impact on CD8 T-cell proliferation, survival, or cytolytic function, which could contribute to the preserved GVL effect mediated by T cells deficient for miR-17-92. Furthermore, we evaluated a translational approach and found that systemic administration of antagomir to block miR-17 or miR-19b in this cluster significantly inhibited alloreactive T-cell expansion and interferon-γ (IFNγ) production, and prolonged the survival in recipients afflicted with GVHD while preserving the GVL effect. Taken together, the current work provides a strong rationale and demonstrates the feasibility to target miR-17-92 for the control of GVHD while preserving GVL activity after allo-BMT.

Author List

Wu Y, Heinrichs J, Bastian D, Fu J, Nguyen H, Schutt S, Liu Y, Jin J, Liu C, Li QJ, Xia C, Yu XZ

Authors

Yongxia Wu PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Allografts
Animals
Bone Marrow Transplantation
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Graft vs Host Disease
Graft vs Leukemia Effect
Interferon-gamma
Leukemia, Experimental
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
MicroRNAs
Oligonucleotides
T-Lymphocytes